DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status
Claims 14-22 and 31-41 are pending. Claims 14-22, 35, 36, 38 and 41 are withdrawn. Therefore, Claims 31-34, 37, 39 and 40 are examined on the merits.
Election/Restrictions
Applicant’s election without traverse in the reply filed on10/31/2025 is acknowledged. Applicant elects:
a. a patient population having:
i. rheumatoid arthritis as a species of arthritis;
ii. plasma as a species of blood sample;
iii. moderate-to-high disease activity signature as a species of disease activity signature, where the moderate-to-high disease activity signature includes
a) an increased level of metabolites, and
b) cysteinylglycine disulfide, mannose, beta-hydroxyisovalerate, gluconate, glucose as metabolites;
and
b. a therapeutic intervention that includes:
iv. administration of an arthritis drug and adalimumab as a species of arthritis drug.
Claims 14-22, 35, 36, 38 and 41 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 10/31/2025.
Information Disclosure Statement
The Information Disclosure Statement(s) filed 5/8/2023 has been considered by the Examiner. The submission(s) is/are in compliance with the provisions of 37 CFR §§ 1.97 and 1.98. Enclosed with this Office Action is a return-copy of the Forms PTO-1449 with the Examiner’s signature and indication of those references that have been considered.
Claim Objections
Claims 31 and 37 are objected to because of the following informalities:
Claim 31: The term “disease signature” at line 7 should be “disease activity signature”.
Claim 37: The term “disease signature” at line 2 should be “disease activity signature”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112 – Not further limiting
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 37 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 37 depends from Claim 31, wherein said moderate-to-high disease signature comprises (2a) an increased level of metabolites or (2b) a decreased level of metabolites. However, Claim 31 limits the number of metabolites of 2a and 2b to five or more each and includes the same list of metabolites for 2a and 2b. Therefore, Claim 37 fails to further limit the number of metabolites or the options of metabolites, failing to further limit Claim 31. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 31-34, 37, 39, and 40 are rejected under 35 U.S.C. 103 as being unpatentable over
Anderson et al. (J. Proteome Res. 2018, 17, 11, 3780–3790) in view of
Kempeni et al. (EP 3190124, publ. date 2017), taken further in view of
Yang et al. (PLoS One. 2015 Jul 6;10(7):e0132695. doi:10.1371/journal.pone.0132695. eCollection 2015),
Giustarini et al. (Clinical and Experimental Rheumatology 2005; 23: 205-212), and
HMDB metabocard entry Gluconic acid (HMDB0000625; 2017-12-07).
Claimed invention
Claim 31 is drawn to:
A method for treating a mammal having arthritis, wherein said method comprises:
determining that a blood sample from said mammal comprises a moderate-to-high disease activity signature,
wherein said moderate-to-high disease signature comprises (2a) an increased level of five or more metabolites selected from the group consisting of cysteinylglycine disulfide, mannose, beta-hydroxyisovalerate, gluconate, and glucose,
and
(b) administering an arthritis drug (adalimumab) to said mammal or performing surgery to treat said arthritis.
Prior art
Anderson teaches metabolomic profiling in inflammatory arthritis and serum metabolite and metabolic pathways have been shown to correlate with markers of inflammation in rheumatoid arthritis (RA), e.g., CRP (Anderson p. 3782, second column). Anderson further teaches that arthritis involves altered metabolic pathways, including glycolysis and the tricarboxylic acid (TCA) cycle (Anderson p. 3783, second column), branched-chain amino acids (isoleucine, leucine, and valine) (Anderson p. 3787, first column). Anti-TNF therapy is effective for RA treatment (p. 3784, first column) and metabolomic analysis of urine from RA patients prior to commencement of anti-TNF therapy identified higher histamine, glutamine and xanthurenic acid, along with lower levels of ethanolamine as biomarkers of a good response to therapy (Anderson p. 3786). Anderson Tables 1 and 2 identifies metabolites measurable in inflammatory arthritis including glucose, mannose and 3-hydroxyisovalerate (i.e., beta-hydroxyisovalerate) and found that RA has higher leucine and glycine levels as compared to osteoarthritis (Anderson pp. 3783-3784). Anderson teaches altered metabolite levels are detected through analysis of fluid samples (e.g., serum, urine and synovial fluid - see Anderson p. 3782).
While Anderson teaches measurement of glucose, mannose, and beta-hydroxyisovalerate in RA metabolomic profiling and teaches that carbohydrate metabolism and branched-chain amino acid (BCAA) metabolism are altered in RA, Anderson does not expressly teach
the administration of adalimumab for RA or
measuring increased levels of the metabolites in RA including gluconate and cysteinylglycine disulfide as part of a specific five-metabolite panel.
Regarding 1) administration of adalimumab for RA:
The prior art already recognized adalimumab as an effective therapeutic for RA. For example, Kempeni establishes that tumor necrosis factor-alpha (TNFα) plays a central role in the pathophysiology of various autoimmune diseases. See Kempeni 0093. Kempeni discloses that conditions marked by elevated TNFα concentrations in the patient's biological fluids—such as serum, plasma, or synovial fluid—can be identified using an anti-TNFα antibody. See Kempeni 0089. Specifically, in rheumatoid arthritis (RA), TNFα drives tissue inflammation and joint destruction. Consequently, inhibiting this cytokine is a viable therapeutic strategy. See Kempeni 0093. As taught by Kempeni, the human anti-TNFα monoclonal antibody adalimumab (D2E7) is indicated for the treatment of RA in humans. Adalimumab binds to TNFα, inhibiting its activity, and is effective in reducing the symptoms, progression, and structural damage associated with RA. See Kempeni title, abstract; claim 1.
A person of ordinary skill in the art (POSA) would have found it obvious to administer adalimumab to RA patients because Anderson establishes RA as an inflammatory disease with measurable metabolic and biochemical perturbations and Kempeni teaches adalimumab is an established anti-TNFα therapy for RA and targets inflammatory mechanisms underlying the disease state described in Anderson. The combination of Anderson and Kempeni merely applies a known RA therapeutic with a known patient population with RA.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Regarding 2) measuring increased levels of the elected metabolites in RA including gluconate and cysteinylglycine disulfide as part of a specific five-metabolite panel:
Anderson already establishes the routine practice of measuring and analyzing the levels of known metabolites in body fluids in patients treated for RA including measuring levels of glucose, mannose, and beta-hydroxyisovalerate in RA metabolomic profiling. Anderson also teaches that perturbations in carbohydrate metabolism and branched-chain amino acid (BCAA) metabolism are of interest in RA.
Giustarini already recognized that human cells have developed a strong antioxidant defense against pro-oxidant reactions (Giustarini, p. 206, right column). An important chemical barrier against oxidative stress damage is the redox equilibrium of sulfhydryl/disulfides, through which low molecular weight thiols can be reversibly oxidized to disulfides and/or protein mixed disulfides (reacting with cysteine residues in proteins) in response to an oxidative status (Giustarini, p. 206, middle column). Giustarini conducted a study and obtained data to determine the plasma sulfhydryl/disulfides balance in patients with active RA by analyzing all thiol redox species that had been potentially modified as a result of the disease (Giustarini, p. 206, right column). Useful information could derive from these data in that it is known that hyperhomocysteinemia is an important risk factor for vascular diseases, thrombotic events and stroke and, what is more, that cardiovascular disorders are the first cause of death in RA patients (Giustarini, paragraph bridging pp. 210 and 211). Giustarini teaches RA patients are characterized by decreased levels of thiols and increased concentration of disulfide forms of thiols (Giustarini, p. 211, middle column), with some of these parameters closely related to articular damage. Homocystine, cystine and corresponding protein-thiol mixed disulfides could be used as useful markers for the evaluation of the activity of the pathology. The possibility that an alteration in the plasma thiols/disulfides balance is a factor that concurs to the development of the disease (Giustarini, p. 211, middle column).
Yang performed metabolomic profiling of RA synovial fluid and reports detection and quantification of D-glucose and mannose, as well as the gluconate in the form of glucono-δ-lactone, in RA patient samples relative to normal controls (see Yang, p. 5; see also Table 1 at p. 7 and Table S3 attached at end of Yang). Thus, similar to Anderson, Yang expressly discloses glucose, mannose, and a gluconate are measurable metabolites in RA patients. HMDB0000625 establishes that glucono-δ lactone is a cyclic ester of gluconic acid (see HMDB0000625, p.1).
A person of ordinary skill in the art (POSA) would have found it obvious to determine whether levels of the metabolites, glucose, mannose, gluconate, 3-hydroxyisovalerate, and cysteinylglycine disulfide, are increased during RA treatment with adalimumab because Anderson, Yang, and Giustarini teach that RA involves measurable metabolic and redox disturbances and that the recited metabolites are detectable and quantifiable in RA samples. The POSA would have found that monitoring the levels of metabolites identified during RA treatment represents a predictable application of metabolomic analysis to evaluate biochemical changes associated with therapeutic intervention. The claim does not require a novel detection technique or unexpected interaction among the metabolites, but merely the determination of whether their levels increase in RA subjects.
Therefore, the claimed invention as a whole would have been prima facie obvious at the time the invention application was filed.
Claim 32 limits claim 31, wherein said mammal is a human. Kempeni teaches the active is administered to humans. See Kempeni, 0087,0088.
Claim 33 limits claim 31, wherein said arthritis is a rheumatoid arthritis. Claim 39 limits claim 31, wherein said method comprises administering said arthritis drug to said mammal. Claim 40 limits claim 39, wherein said arthritis drug is adalimumab. Kempeni teaches administration of adalimumab to treat RA. See Kempeni throughout.
Claim 34 limits claim 31, wherein said blood sample is a plasma sample. Anderson and Giustarini teach metabolite measurements performed on blood-derived samples including plasma, rendering obvious the limitation that the blood sample is plasma. See Kempeni 0089 and Giustarini, p. 206, right column.
Claim 37 limits claim 31, wherein said moderate-to-high disease signature comprises (2a) an increased level of the metabolites selected from the group consisting of, inter alia, cysteinylglycine disulfide, mannose, beta-hydroxyisovalerate, gluconate, and glucose.
Conclusion
No claims are allowed.
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CHRIS E. SIMMONS
Examiner
Art Unit 1622
/CHRIS E SIMMONS/ Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622